Treating chronic obstructive pulmonary disease (COPD) patients with inhaled glucocorticosteroids has been convincingly shown to increase their risk of pneumonia, but the responsible mechanisms are undefined. Work from this laboratory suggests a possible mechanism, related to the increased numbers of cells dying by apoptosis in the lungs in COPD, especially in emphysema. Uptake of apoptotic cells (efferocytosis) suppresses the ability of alveolar macrophages (AM) to fight infections. By markedly increasing AM efferocytosis, glucocorticoids plus apoptotic cells cause greater immune defects than either stimulus alone. This effect is called glucocorticoid-augmented efferocytosis (GCAE). MicroRNAs (miRNAs) are 19-25 nucleotide-long non-coding RNAs that coordinately target large numbers of genes and reduce their protein products. Preliminary data imply that defective AM function is caused by down-regulation of specific miRNAs by GCAE (but not by apoptotic cells alone or glucocorticosteroids alone). The long-term goal of this project is to develop novel, inhalational treatments, based on transient over-expression of these specifically decreased miRNAs, to reverse defective AM immune function when COPD patients taking inhaled glucocorticoids present with community-acquired pneumonia. This project will use ex vivo investigation of AM from both smoke-exposed mice and human volunteers (including active smokers and patients with COPD), and an established murine model of pneumococcal pneumonia. Its immediate goals are to: (a) confirm that GCAE increases pneumococcal pneumonia risk and severity, and in the process, validate a murine model for testing strategies to reverse those defects; (b) define GCAE-induced defects in human AM functionally and by whole- transcriptome analysis, identifying genes uniquely regulated by the GCAE x pneumococcus interaction; (c) validate and optimize miRNA-over-expression to reverse the adverse effects of GCAE on AM defensive functions. Successful completion of this project could lead to more precisely personalized therapies and better outcomes in COPD, currently the third leading cause of death in the USA, and the most expensive-to-treat chronic disease on a per-case basis among Veterans.